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Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing
Author(s) -
Ferguson Sarah E.,
Aronson Melyssa,
Pollett Aaron,
Eiriksson Lua R.,
Oza Amit M.,
Gallinger Steven,
LernerEllis Jordan,
Alvandi Zahra,
Bernardini Marcus Q.,
MacKay Helen J.,
Mojtahedi Golnessa,
Tone Alicia A.,
Massey Christine,
Clarke Blaise A.
Publication year - 2014
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.28933
Subject(s) - lynch syndrome , msh6 , microsatellite instability , medicine , msh2 , mlh1 , germline mutation , endometrial cancer , family history , genetic testing , oncology , cancer , gynecology , mutation , dna mismatch repair , genetics , biology , colorectal cancer , microsatellite , gene , allele
BACKGROUND Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing. METHODS A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS‐associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies. RESULTS A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%. CONCLUSIONS The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014;;120:3932–3939 . © 2014 American Cancer Society .